This invention relates to new and useful aqueous anti-inflammatory compositions suitable for pharmaceutical formulation. More particularly, it is concerned with certain novel aqueous piroxicam solutions which all contain D-(-)-N-methylglucamine and are of value for therapeutic administration.
Piroxicam, i.e., 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, is a known non-steroidal anti-inflammatory agent described and claimed by J. G. Lombardino in U.S. Pat. No. 3,591,584. Piroxicam is sold in capsule form worldwide and it is recognized to be a potent long-acting drug that ensures an effective piroxicam blood level when administered orally once a day. However, there are times when it is desirable to administer the drug parenterally and this can often give rise to some problems, especially since piroxicam is only sparingly soluble in water and thus does not readily lend itself to the formation of solutions.
As can be readily seen from West German Offenlegungsschrift No. 3,217,315 A1, it is for this reason that it has only so far been possible to administer various oxicam derivatives (a category which includes piroxicam) via the oral route of administration. It is also known from this publication that the solubility of piroxicam can be improved slightly via salt formation with equimolar amounts of N-methyl-D-glucamine (a reaction which is also taught for certain other oxicam derivatives in U.S. Pat. No. 4,233,299). Moreover, in the case of the oxicam solutions per se, there is also the additionally serious problem concerning their physical instability so that even if such compounds or their salts dissolve in the appropriate solvent, these solutions tend to precipitate the active ingredients after a short period of time. In West German Offenlegungsschrift No. 3,217,315 A1, there is proposed a solution to this problem which involves increasing the stoichiometric base amount of 1:1 known for the production of organic salts and, if necessary, also adding a pharmaceutically acceptable organic solvent which is freely-miscible with the water. In this way, it is possible to obtain highly-concentrated solutions of piroxicam, e.g., say up to 30% by weight, which remain stable even after a long period of storage and show no separation of the active substances therefrom, especially when N-methyl-D-glucamine is used as a base. Accordingly, West German Offenlegungsschrift No. 3,217,315 A1 discloses piroxicam-containing pharmaceutical preparations, characterized in that they also contain an amount of organic base which is more than one molar with respect to piroxicam and further characterized in that N-methyl-D-glucamine is a preferred base.
The present invention is based on the finding that solutions of piroxicam, and particularly diluted aqueous solutions of same, exhibit chemical instability, i.e., piroxicam can easily be destroyed by way of hydrolysis and/or oxidation, with the assessed product of decomposition being 2-aminopyridine. Additionally, piroxicam has even been found to smell like pyridine under these same conditions. Thus, even though applicant has found that it is possible to obtain suitable injectable solutions of piroxicam by the use of a proper admixture of solvents (organic and aqueous) and the correct adjustment of the pH value in order to overcome the solubility problems of piroxicam, the chemical instability of such solutions still remains and so creates further difficulties.